Background: Cortical reorganization has been shown to occur in the adult central nervous system. Plasticity contributes to various forms of human behavior including learning and memory, different forms of short and long term retention and skill acquisition. Understanding of the role of these different processes in human behavior and of the mechanisms underlying these various forms of human plasticity in the healthy central nervous system represents an important scientific problem. Findings this year: Several important advances have been implemented in this period on our understanding of mechanisms of human motor neuroplasticity and in the development of strategies to enhance it in healthy subjects. Most recently we advanced out understanding of reconsolidation in the human motor cortex by demonstrating that primary cortical processing in the human brain interacting with pre-existent reactivated memory traces is critical for successful modification of the existing related memory. In relation to the importance of practice schedule on motor memory formation, we documented a differential contribution of the supplementary motor area to the stabilization of motor memories acquired through different practice schedules. More generally, our results indicate that the anatomical substrates underlying motor-memory stabilization (or their temporal operation) do differ depending on the practice schedule. We gained insight into the mechanisms underlying successful intermanual transfer of motor learning. We found that practice of a pinch force sequence task resulted in significant improvements in both speed and accuracy in the right trained hand and in the left untrained hand of healthy subjects. RC increased in the left primary motor cortex (M1), GABAergic mediated short intracortical inhibition (SICI) decreased in both M1s, and inter-hemispheric inhibition (IHI) from the left to the right M1 decreased, suggesting that some neurophysiological mechanisms operating in the M1 controlling performance of an untrained hand may contribute to optimize the procedure for selecting and implementing correct pinch force levels. These results raise the hypothesis of a contribution of modulation of SICI and IHI, or an interaction between both to intermanual transfer after learning a sequential pinch force task. In a functional MRI study, we reported that activity in certain non-primary motor areas like the supplementary motor area (SMA) might reflect sensorimotor processes operating in association with mirroring and suggest caution when interpreting fMRI activity in studies that involve unilateral force generation tasks in the absence of simultaneous bilateral EMG/kinematics measurements, a methodological strength of this investigation. In another investigation, we reported that preconditioning right M1 with 1 Hz rTMS significantly decreased the excitability enhancing effects of subsequent left M1 iTBS on recruitment curves. 1Hz rTMS over right M1 alone and iTBS over left M1 alone resulted in increased recruitment curves in left M1 relative to sham interventions. The importance of these findings is that they support the hypothesis that homeostatic mechanisms operating across hemispheric boundaries contribute to regulate motor cortical function in the primary motor cortex. Motor skills can take weeks to months to acquire and can diminish over time in the absence of continued practice. In one study, we report that when healthy subjects practiced over 5 consecutive days while receiving transcranial direct current stimulation (tDCS) over the primary motor cortex, there was greater total (online plus offline) skill acquisition with anodal tDCS compared to sham, which was mediated through a selective enhancement of offline effects. Anodal tDCS did not change the rate of forgetting relative to sham across the three-month follow-up period, and consequently the skill measure remained greater with anodal tDCS at three months. This prolonged enhancement holds promise for the rehabilitation of brain injury. Furthermore, these findings support the existence of a consolidation mechanism, susceptible to anodal tDCS, that contributes to offline effects but not to online effects or long-term retention. In one additional study, we demonstrated that anodal tDCS applied over M1 can facilitate performance of skilled hand functions required for activities of daily living in elderly subjects. Interestingly, despite its increasing use in experimental and clinical settings, the cellular and molecular mechanisms underlying transcranial direct current stimulation (tDCS) remain unknown. Anodal tDCS applied to human motor cortex (M1) improves motor skill learning, suggesting a role for synaptic plasticity. In one study, we demonstrated in mouse M1 slices that DCS induces a long-lasting synaptic potentiation (DCS-LTP), which is polarity-specific, NMDA-receptor dependent and requires coupling of DCS with repetitive low-frequency synaptic activation (LFS). BDNF is a key mediator of this phenomenon, as combined DCS and LFS enhance BDNF-secretion and TrkB-activation, and DCS-LTP is absent in BDNF and TrkB mutant mice. Moreover, the BDNF val66met polymorphism known to partially affect activity-dependent BDNF secretion impairs motor skill acquisition in humans and mice. Motor learning is enhanced by anodal tDCS, as long as activity-dependent BDNF secretion is in place. We proposed that tDCS may improve motor skill learning through augmentation of synaptic plasticity that requires BDNF-secretion and TrkB-activation within M1.